1. Field of the Invention
This invention pertains to dosage forms and methods for providing effective therapy to patients in need of treatment with reboxetine. In particular, the invention is directed to dosage forms and methods for providing sustained release of reboxetine such that once-a-day administration provides effective therapy.
2. Description of the Related Art
All patents and references cited herein are incorporated by reference in their entirety as though fully reproduced herein.
Substituted morpholine derivatives having central nervous system activity and, in particular, antidepressant activity, have been described in U.S. Pat. No. 4,229,449, which is incorporated herein by reference in its entirety. The first compound of this class to be developed as an antidepressant agent is reboxetine having the chemical name 2-[xcex1(2-ethoxyphenoxy)benzyl]morpholine. Reboxetine differs from other available antidepressants by being a selective norepinephrine uptake inhibitor. The evidence suggests that reboxetine is at least as effective as the well-established tricyclic antidepressants and may be as effective as the newer selective serotonin reuptake inhibitors. In addition, reboxetine is well tolerated and appears to have lower potential for adverse drug interactions than some other antidepressants.
U.S. Pat. No. 5,804,209 describes pharmaceutical compositions containing bioadhesive starches and drugs, including, inter alia, reboxetine, primarily for the delivery of drug by the nasal route, although other routes of administration are mentioned. The bioadhesive nature of the starches is described as increasing the time at which the drug remains at the absorption site as compared to drug released from non-bioadhesive compositions. U.S. Pat. Nos. 6,028,070; 6,046,193; and 6,066,643 describe, respectively, a method that uses reboxetine to treat oppositional defiant disorder, a method that uses reboxetine to treat attention-deficit disorder, and pharmaceutical compositions and methods using reboxetine in combination with moxonidine.
Reboxetine methanesulfonate, a pharmaceutically acceptable salt form of the drug, has been available outside of the United States in an immediate-release oral dosage form product of Pharmacia and Upjohn Co. and is currently being evaluated for marketing in the United States. In general, immediate-release dosage forms release essentially the entire dose of drug within a very short period, i.e., minutes, following administration. As this bolus of released drug is absorbed, the plasma drug concentration typically rapidly rises to a maximal or peak concentration and subsequently declines as the drug undergoes xe2x80x9cclearance,xe2x80x9d i.e., becomes distributed, bound or localized within tissues, biotransformed and/or excreted. The rate of drug clearance depends on many factors but will generally be characteristic of a particular drug and may be described by a parameter known as the drug elimination half-life, txc2xd, defined as the time period during which the plasma drug concentration will decline by one half. Generally, during some portion of the time period in which the plasma drug concentration rises, peaks and subsequently declines, the drug provides its therapeutic effects, i.e., the plasma drug concentration achieves or exceeds a therapeutically effective concentration for the disease or condition being treated. Moreover, at some point during this time period, the therapeutic effects disappear, i.e., when the plasma drug concentration declines to a level that is below a therapeutically effective concentration. In addition, during a portion of this time period surrounding the time the peak concentration is attained, i.e., when the plasma drug concentration is in its highest range, undesired side effects of the drug may often become manifest.
Upon administration of each subsequent dose of the immediate-release dosage form, the plasma drug concentration again rapidly rises to a peak concentration and subsequently declines. When a constant drug dose and dosage form is continuously administered at constant intermittent dosing intervals, a pattern of drug accumulation occurs wherein a xe2x80x9csteady-statexe2x80x9d of plasma drug concentrations is eventually achieved. The steady-state condition is characterized by a pattern of rising and falling plasma drug concentrations following each administered dose that repeats identically during each dosing interval. The repeating peaks and troughs can be averaged to determine the average steady-state plasma drug concentration that is maintained in the patient. The drug dose, the release rate of the drug dosage form and the length of the dosing interval affect the magnitude of the steady-state plasma concentration peaks and troughs attained in each dosing interval. For drugs administered in immediate-release dosage forms, relatively high peak plasma concentrations following administration generally cannot be avoided. Accordingly, doses and dosing intervals must be selected to obtain an acceptable balance between attaining average steady-state plasma drug concentrations that provide effective therapy and avoiding, as much as possible, problematical peak and/or trough plasma concentrations during each dosing interval.
The effectiveness of antidepressant therapy generally depends on long-term, continuous use of the drug administered at appropriate intervals to maintain a therapeutically effective average steady-state plasma drug concentration during each dosing interval. Antidepressant agents, in general, may be associated with troublesome dose-dependent side effects when peak plasma drug concentrations are relatively high while periods of loss of efficacy may be associated with low trough plasma drug concentrations. Accordingly, manageable dosing intervals suitable for the available dosage strengths for a particular dosage form must be selected to obtain a satisfactory balance between attaining average steady-state plasma drug concentrations that provide effective therapy and avoiding, as much as possible, problematical peak and/or trough plasma concentrations during each dosing interval.
The presently known immediate-release reboxetine dosage form must be administered at least two times per day, i.e., every 12 hours, to provide average steady-state plasma reboxetine concentrations sufficient for therapeutic effectiveness. Drug is rapidly released from the immediate-release dosage form resulting in relatively high peak plasma drug concentrations following each dose. The twice a day administration schedule results in two occurrences of these peak plasma drug concentrations each day. Accordingly, dose-related side effects, such as orthostatic hypotension, that may occur during the time period surrounding the time of these peak plasma drug concentrations may occur twice during each 24 hour period in patients administered conventional reboxetine therapy, i.e., twice-daily doses of immediate release reboxetine.
In view of the above, it would be an advance in the art to provide methods and apparatus for providing patients with effective steady-state plasma reboxetine concentrations while providing relatively lower peak plasma reboxetine concentrations within each dosing interval. In this manner, the potential for peak-associated problems is minimized. In addition, it would be an advance to provide methods and apparatus for providing patients with effective steady-state plasma reboxetine concentrations while providing fewer peak plasma concentrations per day, i.e., by providing an extended dosing interval of, preferably, 24 hours. In this manner, only one peak plasma drug concentration occurs each day thereby also minimizing the potential for any peak-associated problems. Moreover, a once-a-day dosing schedule results in a simpler and more convenient drug therapy regimen that may improve patient compliance, an especially important consideration for long-term therapies such as antidepressant therapy.
Dosage forms for the sustained release of many different pharmaceutical agents are known in the art, however, no such dosage forms or methods for reboxetine are known. While a variety of sustained release dosage forms for delivering certain drugs may be known, not every drug may be suitably delivered from those dosage forms because of various factors including drug solubility, absorption, metabolism and other physical, chemical and physiological parameters that may be unique to the drug and the mode of delivery. Accordingly, a need exists to provide effective dosing methods, dosage forms and devices for once a day dosing of reboxetine.
In one aspect, the invention comprises a sustained release dosage form adapted to release reboxetine, or a pharmaceutically acceptable acid addition salt thereof, at a release rate that results in lower peak plasma reboxetine concentrations following dose administration than are obtained following administration of an immediate-release reboxetine dosage form.
In another aspect, the invention comprises a sustained release dosage form adapted to release reboxetine or a pharmaceutically acceptable acid addition salt thereof, at a release rate such that administration of just one dose per day provides effective reboxetine therapy. In this manner, the number of peak plasma reboxetine concentrations that occur during each 24-hour period is halved compared to the number that occurs with twice-a-day administration of an immediate-release reboxetine dosage form.
Yet another aspect of the present invention comprises methods of administering sustained release reboxetine dosage forms to provide patients with steady-state plasma reboxetine concentrations sufficient to provide effective therapy when administered at dosing intervals of about 24 hours.
A further aspect of the present invention comprises methods of administering sustained release reboxetine dosage forms to provide patients with sufficient steady-state plasma reboxetine concentrations for about 24 hours while providing peak plasma reboxetine concentrations that occur at a later time following dose administration and exhibit a lesser magnitude than the peak plasma reboxetine concentration that occurs following administration of an immediate-release reboxetine dosage form.
Yet another aspect of the present invention comprises a sustained release composition of reboxetine and a carrier. The carrier may be a carbohydrate, including maltodextrin and sugars. The composition may be compressed under forces of about 3500 newtons or greater, typically 3500-5000 newtons.
The above-described features and advantages as well as others will become more apparent from the following detailed disclosure of the invention and the accompanying claims.